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Development of a human vasopressin V-1a-receptor antagonist from an evolutionary-related insect neuropeptide
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SYSNO ASEP 0474787 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Development of a human vasopressin V-1a-receptor antagonist from an evolutionary-related insect neuropeptide Tvůrce(i) Di Giglio, M. G. (AT)
Muttenthaler, M. (AU)
Harpsoe, K. (DK)
Liutkeviciute, Z. (AT)
Keov, P. (AU)
Eder, T. (AT)
Rattei, T. (AT)
Arrowsmith, S. (GB)
Wray, S. (GB)
Marek, Aleš (UOCHB-X) RID, ORCID
Elbert, Tomáš (UOCHB-X) RID, ORCID
Alewood, P. F. (AU)
Gloriam, D. E. (DK)
Gruber, C. W. (AT)Číslo článku 41002 Zdroj.dok. Scientific Reports. - : Nature Publishing Group - ISSN 2045-2322
Roč. 7, Feb 1 (2017)Poč.str. 15 s. Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova neuropeptide ; inotocin ; V1aR-antagonist Vědní obor RIV CE - Biochemie Obor OECD Biochemistry and molecular biology Institucionální podpora UOCHB-X - RVO:61388963 UT WOS 000393163800001 EID SCOPUS 85011362911 DOI 10.1038/srep41002 Anotace Characterisation of G protein-coupled receptors (GPCR) relies on the availability of a toolbox of ligands that selectively modulate different functional states of the receptors. To uncover such molecules, we explored a unique strategy for ligand discovery that takes advantage of the evolutionary conservation of the 600-million-year-old oxytocin/vasopressin signalling system. We isolated the insect oxytocin/vasopressin orthologue inotocin from the black garden ant (Lasius niger), identified and cloned its cognate receptor and determined its pharmacological properties on the insect and human oxytocin/vasopressin receptors. Subsequently, we identified a functional dichotomy: inotocin activated the insect inotocin and the human vasopressin V-1b receptors, but inhibited the human V1aR. Replacement of Arg8 of inotocin by D-Arg8 led to a potent, stable and competitive V1aR-antagonist ([D-Arg8]-inotocin) with a 3,000-fold binding selectivity for the human V1aR over the other three subtypes, OTR, V1bR and V2R. The Arg8/D-Arg8 ligand-pair was further investigated to gain novel insights into the oxytocin/vasopressin peptide-receptor interaction, which led to the identification of key residues of the receptors that are important for ligand functionality and selectivity. These observations could play an important role for development of oxytocin/vasopressin receptor modulators that would enable clear distinction of the physiological and pathological responses of the individual receptor subtypes. Pracoviště Ústav organické chemie a biochemie Kontakt asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Viktorie Chládková, Tel.: 232 002 434 Rok sběru 2018 Elektronická adresa https://www.nature.com/articles/srep41002
Počet záznamů: 1